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Rhodium-Catalyzed Stereoselective Intramolecular Tandem Reaction of Vinyl Oxiranes with Alkynes: Atom- and Step-Economic Synthesis of Multifunctional Mono-, Bi- and Tri-Cyclic Compounds Jian-Jun Feng, and Junliang Zhang ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b03399 • Publication Date (Web): 13 Jan 2017 Downloaded from http://pubs.acs.org on January 13, 2017
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ACS Catalysis
Rhodium-Catalyzed Stereoselective Intramolecular Tandem Reaction of Vinyl Oxiranes with Alkynes: Atom- and StepEconomic Synthesis of Multifunctional Mono-, Bi- and TriCyclic Compounds Jian-Jun Feng* and Junliang Zhang* Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 3663 N. Zhongshan Road, Shanghai 200062, P. R. China. ABSTRACT: Skeletal diversity in diversity-oriented synthesis has proven to be especially challenging. A rhodium-catalyzed intramolecular tandem reaction of vinyl oxirane-alkynes leading to four structurally distinct classes of mono-, bi- and tri-cyclic carbocycles and heterocycles was developed. [Rh(NBD)2]+ BF4- is identified to be efficient catalyst for these transformations. Using this highly efficient catalyst, hetero-[5+2] cycloadditions, tandem hetero-[5+2] cycloaddition/Claisen rearrangement and subsequent cyclopropane ring opening reactions of vinylic oxiranes with mono-alkynes afford 2,5-dihydrooxepins, tetrasubstituted vinylcyclopropanes and multifunctional five-membered rings, respectively, under mild conditions with high stereoselectivity and yield. Moreover, hetero-[5+2] cycloaddition/Claisen rearrangement/[5+2] cycloaddition reaction of vinylic oxiranes with diynes for stepeconomic construction of linearly fused 5-7-5 tricyclic skeletons has also been developed. The complete transfer of chirality from readily available vinylic oxiranes to the corresponding products provides a highly efficient and practical access to these chiral cyclic compounds. KEYWORDS: Rhodium, tandem reaction, vinylic oxirane, alkyne, diversity-oriented synthesis, chirality transfer
1. INTRODUCTION The design or discovery of new versatile building blocks is of preeminent importance to the realization of the diversityoriented synthesis (DOS).1 Cyclopropanes, cyclopentenes, 2,3dihydro-1H-pyrroles, 2,3-dihydrofurans, oxepines and linearly fused 5-7-5 tricyclic skeletons are ubiquitous structural motifs found in an array of natural products and pharmaceuticals with diverse biological and medicinal properties (Figure 1).2 Therefore, the development of highly efficient synthetic methods to access these skeletons has been intensively pursued by synthetic community.3 However, the widely applied approaches for construction of these three-, five- and seven-membered carbocycles and heterocycles require building each ring independently from different building blocks. Thus, the development of an ideal method for construction of these diverse scaffolds from a common building block in an atom- and stepeconomic fashion is extremely interesting and highly desirable.4 Modern transition metal-catalyzed cycloaddition reactions represent powerful tools enabling quick and efficient access to mono-, bi- and tricyclic structures from relatively simple starting materials.5 In particular, using small-ring compounds as cycloaddition partners brings opportunities for developing novel reactions that complement to or surpass traditional cycloadditons.6,7 Among them, vinylcyclopropanes (VCPs) represent an important subclass of activated cyclopropane derivatives with rich cycloaddition chemistry.7 For example, Wender’s group pioneered the development of Rh-catalyzed [5+2] cycloadditions of VCPs and π-systems for synthesis of seven-membered rings.8 Subsequently, the research groups of
Figure 1. Representative biologically active three-, five- and seven-membered carbocycles and heterocycles.
Trost,9 Louie,10 Fürstner11 have realized the [5+2] cycloadditions of VCPs and alkynes by using different transition-metal catalysts. [5+2+1],12 [5+1],13 [5+1+2+1]14 cycloadditions have also been developed for constructing different cyclic systems in which VCPs serving as five-carbon synthons. The VCP motif can also act as an activated cyclopropane ring (threecarbon synthon) to undergo [3+x] cycloadditions, Tsuji,15a Trost,15b-c Yu,15d-i and others15j-m have done seminal work on this kind of cycloadditions. The significance of the VCPs has been highlighted in the synthesis of several natural products by using [5+x] and [3+x] cycloadditions.7c,16 Due to the inherent reactivity of their constrained ring system, cyclopropane and oxirane derivatives constitute valuable building blocks for organic synthesis.17 In contrast to VCPs, vinyl oxiranes18, one of versatile synthons of oxirane deriva-
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tives, have and continue to serve as attractive ring-expansion motifs in metal-catalyzed [3+2] cycloadditions,19 epoxide carbonylation20 and substitution reactions.21 Recently, an elegant system for copper-catalyzed rearrangement of vinylic oxiranes to 2,5-dihydrofurans has been developed by Njardarson group.22 However, there has been no report about utilizing vinyl oxiranes as a hetero five-atom partner in cycloaddition reaction until we reported an atom-economic route to multisubstituted VCPs relying upon a new synthetic application of vinylic oxiranes in a rhodium-catalyzed intramolecular hetero[5+2] cycloaddition/Claisen rearrangement reaction.23 Although many five-carbon components have been developed,8m, 24 cyclopropylimines had been the only heteroatom-containing five-atom component in Rh-catalyzed hetero-[5+2] cycloaddition prior to our study.25a,b Considering that the product of hetero-[5+2] cycloaddition/Claisen rearrangement reaction is the multifunctional VCPs and the rich chemistry of VCPs,7,8 we became interested in whether vinylic oxirane-alkynes 1 could be used as a common precursor to build structurally distinct compounds and tuning the selectivity by the subtle choice of catalyst and modification of the substrate. Scheme 1. Diversity-Oriented Synthesis of Three-, Five and Seven-Membered Rings from Vinyl Oxirane-Alkynes
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[5+2]cycloaddition/Claisen rearrangement/[5+2] cycloaddition reaction of vinyl oxiranes with diynes for construction of 5-75 tricyclic compounds in one step (Scheme 1d). In addition, enantioselective synthesis of these compounds from optically pure vinyl oxiranes via a chirality transfer process was achieved and mechanistic studies have also been investigated. Of note, while other catalyst-selective synthesis systems are known,26 we know few being capable of delivering the level of skeletal diversity by simply varying the reaction temperature and using a single catalyst. 2. RESULTS AND DISCUSSION 2.1 [Rh(NBD)2]+BF4- catalyzed hetero-[5+2] cycloaddition and tandem hetero-[5+2] cycloaddition/Claisen rearrangement reaction of vinyl oxiranes with mono-alkynes Oxepine derivatives represent a ubiquitous class of oxygencontaining heterocycles with wide occurrence in numerous biologically active natural products and pharmaceuticals, such as Lobatrienetriol, Zoapatanol, and Stellettasterenol (Figure 1).2 However, relative to reactions that establish five- and sixmembered oxygen-heterocycles, the development of efficient methodology for construction of oxepine skeletons is often much more difficult because of the unfavorable entropic factors and transannular interactions.27 Table 1. [Rh(NBD)2]+BF4--Catalyzed Hetero-[5+2] Cycloaddition Reactiona entry
substrate
yield (%)b
product
1c
72 1a
2a
1b
2b
1c
7c
2c
75
3d
56
4d
In previous examples,23 we found that RhCl(IPr)(COD) /AgSbF6 bearing a strong σ-donating IPr ligand can catalyze the hetero-[5+2] cycloaddition/Claisen rearrangement reaction at 60-84 oC. Because the Claisen rearrangement of 2 to 3 is a rapid process under thermal conditions, it is very hard to obtain the hetero-[5+2] cycloadducts 2. With respect to substrate scope, the alkyne moiety of 1 was limited to internal alkyne. In this article, we demonstrate the details of the development of this hetero-[5+2] cycloaddition/Claisen rearrangement reaction and expansion of its substrate scope to both trimethylsilyl alkyne and terminal alkynes by using [Rh(NBD)2]+BF4-as the catalyst (Scheme 1b). Furthermore, We also found that [Rh(NBD)2]+BF4- is an efficient catalyst for catalyzing this reaction at room temperature, which give an opportunity to obtain the hetero-[5+2] cycloaddition product, i.e. 2,5dihydrooxepin 2 (Scheme 1a). We also disclose two new [Rh(NBD)2]+BF4-catalyzed cascade reactions: 1) hetero-[5+2] cycloaddition/Claisen rearrangement/cyclopropane ring opening reaction of vinyl oxiranes with mono-alkynes leading to multifunctional five membered rings (Scheme 1c); 2) hetero-
65 1d
7d
a
Conditions A: 1 (0.2 mmol), [Rh(NBD)2]+BF4- (5 mol%), in CH2Cl2 (0.08 M) at 0 oC. b Isolated yield. c The reaction was run at
20 oC. d the corresponding hetero-[5+2] cycloadduct was treated with 10 % Pd/C and H2 (1atm).
During our investigation of Rh(I)-catalyzed cycloaddditions of vinylaziridines with π-systems,28 we found that the cationic rhodium(I) complex [Rh(NBD)2]+BF4- is a convenient and highly effective catalyst for the intramolecular hetero[5+2] cycloaddition of vinylaziridines and a wide range of terminal and internal alkynes. Atom analogy suggests that vinyl oxirane-alkynes could be analogously activated by [Rh(NBD)2]+BF4- to generate fused oxepine derivatives. Although this assumption was first validated by us in 2011, the use of first-generation catalyst (RhCl(IPr)(COD)/AgSbF6) makes it very hard to intercept of hetero-[5+2] cycloadducts 2, due to the rapid Claisen rearrangement of 2 to vinylcyclopropane derivative 3 under thermal conditions. For example, sub-
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strate 1a in presence of 5 mol% of RhCl(IPr)(COD)/AgSbF6 in DCE for 4 h at 84 oC, gave only 9% NMR yield of the hetero[5+2] cycloadduct 2a with the further Claisen rearrangement products 3a and 6a in 83% total NMR yield (eq 1).23 Moreover, the previous tandem hetero-[5+2] cycloaddition/Claisen rearrangement reaction of vinyl oxiranes with mono-alkynes under the catalysis of RhCl(IPr)(COD)/AgSbF6 is limited to internal alkynes. Thus, the development of the secondgeneration catalyst to broaden the substrate scope under mild reaction conditions and intercept the hetero-[5+2] cycloadduct is highly desirable.
To our delight, as depicted in Table 1, subjection of 1a and 1b to the mixture of 5 mol% [Rh(NBD)2]+BF4- in CH2Cl2 at 20 o C afforded the desired products 2a and 2b in 72% and 75% yields, respectively (Table 1, entries 1 and 2). It was found that 2,5-dihydrooxepin products were not stable at room temperature for prolonged reaction time, because of the enol ether moiety. To facilitate easy characterization, the hetero-[5+2] cycloadducts 2c and 2d were further treated with 10 % Pd/C and H2, delivering the fully saturated oxepanes 7c and 7d in acceptable yield over two steps (Table 1, entries 3 and 4). Table 2. [Rh(NBD)2]+BF4--Catalyzed Tandem Hetero-[5+2] Cycloaddition/Claisen Rearrangement Reactiona R4
R4 R1
X
5 mol% O 1
R2
[Rh(NBD) 2] +BF4-
R4 R4
R1 O H
X
DCE / RT R3
3
H 3 R
R2
R1/R2/R3/R4 (1)
t (h)
C(CO2Me)2
Ph/Ph/H/H (1e)
5
3e (92)
2
C(CO2Me)2
4-MeOC6H4/Ph/H/H(1f)
7
3f (89)
3
C(CO2Me)2
4-ClC6H4/Ph/H/H (1g)
7
3g (72)
C(CO2Me)2
4-ClC6H4/Ph/H/H (1g)
5
3g (50)
5
C(CO2Me)2
TMS/Ph/H/H (1h)
2
3h (64)
6c
C(CO2Me)2
TMS/Ph/H/H (1h)
5
3h (
